Project Summary/Abstract The prevalence of heart attacks has increased among women between 35-50 years of age compared to men of the same age. In contrast to men, women have a higher risk of mortality and complications after a heart attack due to the under-representation of women in clinical trials, the lack of gender-tailored pharmacological treatments, and potential higher vulnerability of women than for men to traditional and emerging risk factors. Stress has emerged as an important risk factor for heart disease in women; stress levels have been shown to correlate with delayed recovery, recurrence, and increased mortality after a heart attack in women. Sex hormones are considered the critical regulators of the physiological differences between men and women in health and disease. These hormones certainly contribute to sexual dimorphism in heart disease; however, the effects of gender on the incidence and outcomes of a heart attack are more complex and are unlikely to be due to sex hormones alone. The goal of the present proposal is to define one of the signaling pathways underlying the deleterious effects of stress on female cardiac health in the setting of myocardial ischemia (heart attack). To accomplish this goal, we propose to investigate the mechanisms whereby glucocorticoids (the primary stress hormones) affects estrogen cardioprotection in myocardial ischemia by repressing serotonin activity in cardiomyocytes via glucocorticoid inhibition of estrogen transcriptional regulation of the serotonin receptor 5- HT2BR (implicated in cardioprotection through the regulation of mitochondrial function in cardiomyocytes). A decrease in serotonin activity has been associated with increased risk of myocardial infarction in depressed patients, and also polymorphisms in serotonin receptors are associated with elevated glucocorticoid response linked to cardiovascular complications, including an increased incidence of heart attacks. Therefore, we aim to elucidate estrogen regulatory mechanism of 5-HT2BR expression in the heart and the effects of glucocorticoids on estrogen-mediated 5-HT2BR signaling in ischemia/reperfusion (I/R). We hypothesize that stress exerts deleterious effects on the female heart in myocardial infarction by exacerbating mitochondrial dysfunction via glucocorticoids inhibition of estrogen transcriptional regulation of 5-HT2BR in cardiomyocytes. We will investigate this pathway by examining glucocorticoid and estrogen antagonism in cardiomyocytes, the effects of this crosstalk in I/R (in vivo studies), and the molecular and physiological effects of 5-HT2BR regulation by estrogen in mitochondrial function in ischemic conditions. If funded, this application will help me develop a scientifically independent project, acquire training in the cardiovascular field, build a research team, enhance my mentoring skills, and improve my grant writing skills to become competitive to apply to a major funding mechanism. My current institution and my mentor and co-mentor will provide me with the necessary facilities and guidance to accomplish these goals. Also, I will participate in training and career development activities that will strengthen my scientific career.